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EP0673240B1 - Stabilized medicinal aerosol solution formulations - Google Patents

Stabilized medicinal aerosol solution formulations Download PDF

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Publication number
EP0673240B1
EP0673240B1 EP94903467A EP94903467A EP0673240B1 EP 0673240 B1 EP0673240 B1 EP 0673240B1 EP 94903467 A EP94903467 A EP 94903467A EP 94903467 A EP94903467 A EP 94903467A EP 0673240 B1 EP0673240 B1 EP 0673240B1
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EP
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Prior art keywords
acid
aerosol solution
wght
solution formulation
formulation according
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German (de)
French (fr)
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EP0673240A1 (en
Inventor
Paul D. Jager
Mark J. Kontny
Jurgen H. Nagel
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Boehringer Ingelheim Pharmaceuticals Inc
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Boehringer Ingelheim Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators

Definitions

  • This invention relates to stable pharmaceutical solution formulations suitable for aerosol administration. More particularly, this invention relates to stable pharmaceutical solution formulations suitable for aerosol administration wherein either an inorganic acid or an organic acid is added to the aerosol solution formulation which contains a medicament in solution with an environmentally safe hydrofluorocarbon (HFC) as a propellant, together with an organic compound as a cosolvent.
  • HFC hydrofluorocarbon
  • the acid provides stability against degradation or decomposition of the medicament resulting largely from interaction of the medicament with the cosolvent and/or water present in the solution formulation.
  • aerosol formulations of medicaments by means of pressurized, metered-dose inhalers (MDIs) is used widely in therapy, such as in the treatment of obstructive airway diseases and asthma.
  • MDIs pressurized, metered-dose inhalers
  • inhalation provides more rapid onset of action while minimizing systemic side effects.
  • Aerosol formulations can be administered by inhalation through the mouth or topically by application to the nasal mucosa.
  • Formulations for aerosol administration via MDIs can be solutions or suspensions.
  • Solution formulations offer the advantage of being homogeneous in nature with the medicament and excipient completely dissolved in the propellant vehicle. Solution formulations also obviate physical stability problems associated with suspension formulations and thus assure more consistent uniform dosage administration while also eliminating the need for surfactants.
  • the administration of aerosol solution formulations via MDIs is dependent upon the propulsive force of the propellant system used in its manufacture.
  • the propellant comprised a mixture of chlorofluorocarbons (CFCs) to provide the desired solubility, vapor pressure, and stability of the formulation.
  • CFCs chlorofluorocarbons
  • HFC hydrofluorocarbon
  • 4,174,295 discloses the use of propellant systems consisting of combinations of HFCs, which may also contain a saturated hydrocarbon component, suitable for application in the fields of home products such as hair lacquers, anti-perspiration products, perfumes, deodorants, paints, insecticides and the like.
  • HFC-134(a) 1,1,1,2-tetrafluoroethane
  • Adjuvant a compound having a higher polarity than the HFC-134(a)
  • W091/11496 discloses the use of 1,1,1,2,3,3,3-heptafluoropropane (HFC-227), optionally mixed with other propellant components, for use in preparing suspension aerosol formulations of medicaments.
  • US-A-2 868 641 and US-A-3 282 781 disclose aerosol compositions comprising a medicament (epinephrine or isoproterenol HCl), a cosolvent, a propellant and ascorbic acid as anti-oxidant.
  • a medicament epinephrine or isoproterenol HCl
  • cosolvent epinephrine or isoproterenol HCl
  • propellant epinephrine or isoproterenol HCl
  • ascorbic acid as anti-oxidant
  • aerosol suspension formulation means a pharmaceutical formulation of a medicament suitable for aerosol administration wherein the medicament is suspended, in the form of finely, divided particles, in an excipient.
  • aerosol solution formulation means a pharmaceutical formulation of a medicament suitable for aerosol administration wherein the medicament and excipients are completely dissolved.
  • stable aerosol solution formulation means an aerosol solution formulation which exhibits substantial chemical stability over time.
  • Ipratropium bromide is an anticholinergic bronchodilator marketed under the trademark "ATROVENT.”
  • This medicament is administered as an aerosol suspension formulation which contains a mixture of CFCs (dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane) as the propellant, and soya lecithin.
  • ipratropium bromide can be obtained by dissolving ipratropium bromide in a homogeneous system comprising HFC-134(a), ethanol, and either an inorganic acid or an organic acid.
  • HFC-134(a) a homogeneous system comprising HFC-134(a), ethanol, and either an inorganic acid or an organic acid.
  • the particular type and amount of acid added to the system will define the level of acidity which is critical in obtaining a stable solution formulation.
  • the present invention provides stabilized aerosol solution formulations comprising a medicament, selected from the group consisting of ipratropium bromide, oxitropium bromide, albuterol tiotropium bromide and feneterol an HFC propellant, a cosolvent, and an inorganic acid or an organic acid.
  • a medicament selected from the group consisting of ipratropium bromide, oxitropium bromide, albuterol tiotropium bromide and feneterol
  • an HFC propellant a cosolvent
  • an inorganic acid or an organic acid may also be present in the propellant/cosolvent system.
  • Suitable HFC propellants are those which, when mixed with the cosolvent(s), form a homogeneous propellant system in which a therapeutically effective amount of the medicament can be dissolved.
  • the HFC propellant must be toxicologically safe and must have a vapor pressure which is suitable to enable the medicament to be administered via a pressurized MDI. Additionally, the HFC propellant must be compatible with the components of the MDI device (such as containers, valves, and sealing gaskets, etc.) which is employed to administer the medicament.
  • Preferred HFC propellants are 1,1,1,2-tetrafluoroethane (HFC-134(a)) and 1,1,1,2,3,3,3,-heptafluoropropane (HFC-227).
  • HFC-134(a) is particularly preferred.
  • HFC propellants are HFC-32 (difluoromethane), HFC-143(a) (1,1,1-trifluoroethane), HFC-134 (1,1,2,2-tetrafluoroethane), and HFC-152a (1,1-difluoroethane).
  • non-halogenated hydrocarbon propellants may be used in place of the HFC propellants in the present invention.
  • non-halogenated hydrocarbons are saturated hydrocarbons, including propane, n-butane, and isobutane, and ethers, including diethyl ether.
  • a substantially non-aqueous HFC propellant/cosolvent system is preferred.
  • Water may be present in small amounts as an impurity in the HFC propellant/cosolvent system, may be introduced during the manufacturing process or may permeate into the system through the valve or valve/container seals or gaskets. If desired, small amounts of water may be added (up to about 5% by weight) to the HFC/propellant system, for example, to aid in manufacturing.
  • a soluble surface active agent can be added in order to improve the performance of valve systems employed in the MDI devices used for the aerosol administration of the formulations.
  • preferred surface active agents are oleic acid, sorbitan trioleate, lecithin, and isopropylmyristate.
  • Other suitable lubricants are well known in the art (see, for example, Published European Patent Application No. 0372777 (EPO 893122705)).
  • excipients are: (a) antioxidants, for example ascorbic acid and tocopherol; (b) taste masking agents, for example, menthol, sweeteners, and artificial or natural flavors; and (c) pressure modifying agents, for example, n-pentane, iso-pentane, neo-pentane, and n-hexane.
  • antioxidants for example ascorbic acid and tocopherol
  • taste masking agents for example, menthol, sweeteners, and artificial or natural flavors
  • pressure modifying agents for example, n-pentane, iso-pentane, neo-pentane, and n-hexane.
  • the medicaments used in the present invention are selected from the group consisting of ipratropium bromide, oxitropium bromide, albuterol, tiotropium bromide and feneterol.
  • the medicament must be soluble in the HFC propellant/cosolvent system and, characteristically exhibit significant degradation or decomposition in the HFC propellant/cosolvent system.
  • the degradation or decomposition of the medicament must be acid sensitive in that the rate of degradation or decomposition can be effectively reduced by the addition of acid.
  • the decomposition and the degradation of the medicament may occur by various chemical mechanisms, the most significant being interaction of the medicament with the cosolvent or with the water present in the system to form hydrolysis, esterification, and/or ether products.
  • the amount of medicament employed in the aerosol solution formulations of the present invention is that which is effective in producing the intended therapeutic effect, i.e., an amount such that one or more metered volumes of the formulation will deliver an effective amount of the medicament. It will be apparent to those skilled in the art that the potency of the particular medicament employed in the aerosol solution formulation will determine the amount of medicament in the formulation. In general, the medicament is present in an amount from about 0.001 to 10 percent by weight of the total weight of the formulation. An amount of from about 0.01 to 1.0 percent by weight of the total weight of the formulation is preferred.
  • the most preferred example of the medicaments for use in the aerosol solution formulations of the present invention is ipratropium bromide.
  • Other examples are oxitropium bromide (BA253), albuterol, tiotropium bromide (BA-679), and fenoterol hydrobromide.
  • cosolvent may be any one of a number of organic solvents that are toxicologically safe and amenable to MDI solution formulations.
  • solvent is meant any solvent which is miscible in the formulation in the amount desired and which, when added provides a formulation in which the medicament can be dissolved in therapeutically effective amounts.
  • alcohols for example, ethyl alcohol and isopropyl alcohol
  • glycols for example, propylene glycol, polyethylene glycols, polypropylene glycols, glycol ethers, and block copolymers of oxyethylene and oxypropylene
  • other substances for example, glycerol, polyoxyethylene alcohols, and polyoxtethylene fatty acid esters.
  • cosolvents that may be inert to interaction with the medicament(s) are hydrocarbons, for example, n-propane, n-butane, isobutane, n-pentane, iso-pentane, neo-pentane, and n-hexane; and ethers, for example, diethyl ether.
  • hydrocarbons for example, n-propane, n-butane, isobutane, n-pentane, iso-pentane, neo-pentane, and n-hexane
  • ethers for example, diethyl ether.
  • a preferred cosolvent according to this invention is ethyl alcohol (ethanol).
  • the function of the cosolvent is to increase the solubility of the medicament and the excipients in the formulation.
  • the amount of cosolvent present in the formulation defines the maximum amount of medicament and excipients that can be dissolved at a particular temperature.
  • the selection of the acid in the aerosol solution formulations of this invention depends on the medicament used and the acid concentration needed to effect an acceptable rate of degradation of the medicament. Ideally the preferred acid will have the same anion as that contained in the medicament, if any. However, in some instances, this may present solubility limitations.
  • the acid may be any inorganic or mineral acid, for example, hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid, or the like.
  • the acid may also be selected from the group of acids known to those skilled in the art as organic acids, which are in most cases considered to be weak acids relative to the inorganic acids. Representative of this group and preferred in this invention are ascorbic acid and citric acid, although other organic acids may also be suitable. However, according to this invention, citric acid is the most preferred acid because of MDI component compatibility.
  • an aerosol solution formulation comprising a particular medicament may be formulated using acids selected from either of the above groups.
  • the methods used to introduce the acid into the formulation may include: (1) the direct addition of the inorganic or organic acid; (2) the addition of the medicament as an acidic salt thereby generating the correct acidity level in situ, and (3) combinations of (1) and (2).
  • Appropriate salts for introducing the medicament into the formulation will be apparent to those skilled in the art.
  • a range of chemical compositions is given in Table 1 for aerosol solution formulations containing ipratropium bromide, HFC-134(a), and an inorganic acid, such as hydrochloric, nitric phosphoric, or sulfuric acid.
  • the amount of alcohol present in the formulation defines the maximum amount of ipratropium bromide that can be dissolved at a particular temperature.
  • the range of ipratropium bromide concentrations given in Table 1 is based on the maximum amount that can be safely dissolved without precipitation at room temperature for a given alcohol concentration.
  • Acid content is given in units of normality which defines a pH range equivalent to 2.0 - 4.7 in an aqueous system.
  • Ipratropium Bromide Aerosol Solution Formulations Range Of Chemical Compositions For An Inorganic Acid Formulation Component Contents per MDI Container Ipratropium Bromide as the Monohydrate 0.001 - 25% wght./wght. Dehydrated (Absolute) Ethanol, USP 1.0 - 50.0% wght./wght. 1,1,1,2-Tetrafluoroethane, (HFC-134(a)) (Dupont Pharmaceutical Toxicity Grade) 50.0 - 99.0% wght./wght. Inorganic Acid, USP/NF (Hydrochloric Acid) 0.01 - 0.00002 Normal Water (Purified), USP 0.0 - 5.0% wght./wght.
  • a range of chemical compositions is given in Table 2 for aerosol solution formulations containing ipratropium bromide, HFC-134(a), and the organic acid, ascorbic acid.
  • the range of ascorbic acid concentration presented in Table 2 was based on its acid dissociation constant(s), pKa(s), and the optimal pH range for a stable ipratropium bromide formulation (2.0-4.7) in an aqueous system.
  • 0.0045-275 mg/ml would be required to correspond to an aqueous pH range of 2.0-4.7.
  • solubility limitations in the formulation must also be taken into consideration given the fact that ascorbic acid is only soluble to about 20 mg/ml in absolute ethanol and is expected to have a lesser solubility in an absolute ethanol/HFC-134(a) system.
  • Table 2 The information contained in Table 2 is presented for ascorbic acid and gives a range of ethanol content that is based on the expected room temperature solubility of ipratropium bromide (as the monohydrate).
  • about 0.30 mg/ml of ascorbic acid is expected to be required in such a formulation corresponding to a pH-degradation rate minimum of pH 3.5 for ipratropium bromide in an aqueous system.
  • the range of acid concentration required to effect an acceptable rate of decomposition for medicaments in primarily non-aqueous solution aerosol formulations will depend primarily on the chemical composition of the formulation (such as choice of cosolvent(s) and the chemical nature of the medicaments(s) present). This range is expected to be about 0.10 - 0.0000001 normal for the inorganic acids corresponding to an aqueous pH range of about 1.0-7.0 and must be calculated for the organic acids depending on their pKa values.
  • Ipratropium Bromide Aerosol Solution MDI Formulations Range Of Chemical Compositions For An Organic Acid Formulation Component Contents per Container Ipratropium Bromide as the Monohydrate 0.001 - 2.5% wght./wght.
  • 1,1,1,2-Tetrafluoroethane (HFC-134(a)) (Dupont Pharmaceutical Toxicity Grade) 84.4773% wght./wght. 84.4586% wght./wght. 84.4212% wght./wght. Citric Acid, USP 0.0040% wght./wght. 0.0040% wght./wght. 0.0040% wght./wght. Water (Purified), USP 0.5000% wght./wght. 0.5000% wght./wght. 0.5000% wght./wght. Total 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.0000% 100.000
  • Table 4 gives a chemical composition for an aerosol formulation containing fenoterol hydrobromide, HFC-134(a) and citric acid.
  • Fenoterol Hydrobromide Aerosol Solution Formulation Component Contents per MDI Container Fenoterol Hydrobromide 0.192% wght./wght. Dehydrated (Absolute) Ethanol, USP 30.000% wght./wght. 1,1,1,2-Tetrafluoroethane, (HFC-134(a)) (Dupont Pharmaceutical Toxicity Grade) 67.806% wght./wght. Citric Acid, USP 0.002% wght./wght. Water (Purified), USP 2.000% wght./wght. Total 100.000%
  • the amount of drug in an aerosol solution formulation that can be delivered through the valve of an MDI will depend on the activeingredient concentration (mg/ml) in the formulation and the metering volume (ul) of the valve. Commonly used valve sizes are 25, 50, 63 and 100 ul.
  • Metered dose inhalers containing aerosol solution formulations of medicaments can be manufactured using a number of conventional processing methods.
  • One method, which is useful in the laboratory for the manufacture of small laboratory scale lots, is Dual Stage Pressure Fill. This method is shown in Tables 5 and 6 for two specific ipratropium bromide solution formulations using a 50-ul valve.
  • Two methods for large scale manufacture are Single-Stage Cold Fill and Single-Stage Pressure Fill. Ipratropium Bromide Inhalation Aerosol, 0.021 mg Drug Delivered Through The Valve, 12 ml I.
  • Composition Component Contents per Container Ipratropium Bromide Monohydrate 0.00505 gm Dehydrated (Absolute) Ethyl Alcohol, USP 2.02500 gm 1,1,1,2-Tetrafluoroethane, (HFC-134(a) (Dupont Pharmaceutical Toxicity Grade) 11.40209 gm Nitric Acid, USP/NF 0.00036 gm Water (Purified), USP 0.06750 gm TOTAL: 13.50000 II.
  • the concentrate is added to an appropriate filling apparatus.
  • the active ingredient concentrate is dispensed into aerosol containers.
  • the headspace of the containers is purged with nitrogen or HFC-134(a) vapor (purging ingredients should not contain more than 1 ppm oxygen) and is sealed with valves.
  • the HFC-134(a) propellant is then pressure-filled into the sealed containers.
  • Device Components Suitable Aerosol Container 50 ul Aerosol Metering Valve III. Brief Description of Processing Method An active ingredient concentrate is prepared by dissolving the ipratropium bromide, as the monohydrate, ascorbic acid and water in ethyl alcohol.
  • the concentrate is added to an appropriate filling apparatus.
  • the active ingredient concentrate is dispensed into aerosol containers, the headspace of the containers is purged with Nitrogen or HFC-134(a) vapor (purging ingredients should not contain more than 1 ppm oxygen) and is sealed with valves.
  • the HFC-134(a) propellant is then pressure filled into the sealed containers.

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Abstract

Stabilized medicinal aerosol solution formulations comprising medicaments that degrade or decompose by interaction with solvents or water, an HFC propellant, a cosolvent and an acid are described. Further, specific medicinal aerosol solution formulations comprising ipratropium bromide or fenoterol, ethyl alcohol, 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, and either an inorganic acid or an organic acid are described. The acids are present in amounts sufficient to reduce the degradation of the medicaments to acceptable levels.

Description

  • This invention relates to stable pharmaceutical solution formulations suitable for aerosol administration. More particularly, this invention relates to stable pharmaceutical solution formulations suitable for aerosol administration wherein either an inorganic acid or an organic acid is added to the aerosol solution formulation which contains a medicament in solution with an environmentally safe hydrofluorocarbon (HFC) as a propellant, together with an organic compound as a cosolvent. The acid provides stability against degradation or decomposition of the medicament resulting largely from interaction of the medicament with the cosolvent and/or water present in the solution formulation.
    • BACKGROUND OF THE INVENTION
  • The administration of aerosol formulations of medicaments by means of pressurized, metered-dose inhalers (MDIs) is used widely in therapy, such as in the treatment of obstructive airway diseases and asthma. Compared with oral administration, inhalation provides more rapid onset of action while minimizing systemic side effects. Aerosol formulations can be administered by inhalation through the mouth or topically by application to the nasal mucosa.
  • Formulations for aerosol administration via MDIs can be solutions or suspensions. Solution formulations offer the advantage of being homogeneous in nature with the medicament and excipient completely dissolved in the propellant vehicle. Solution formulations also obviate physical stability problems associated with suspension formulations and thus assure more consistent uniform dosage administration while also eliminating the need for surfactants.
  • The administration of aerosol solution formulations via MDIs is dependent upon the propulsive force of the propellant system used in its manufacture. Traditionally, the propellant comprised a mixture of chlorofluorocarbons (CFCs) to provide the desired solubility, vapor pressure, and stability of the formulation. However, since it has been established in recent years that CFCs are environmentally harmful because they contribute to the depletion of the Earth's ozone layer, it is desirable to substitute environmentally safe hydrofluorocarbon (HFC) propellants or other non-chlorinated propellants for environmentally harmful CFC propellants in aerosol inhalation formulations. For example, U.S. Patent No. 4,174,295 discloses the use of propellant systems consisting of combinations of HFCs, which may also contain a saturated hydrocarbon component, suitable for application in the fields of home products such as hair lacquers, anti-perspiration products, perfumes, deodorants, paints, insecticides and the like.
  • It is known in the art that certain HFCs have properties suitable for use as propellants for the aerosol administration of medicaments. For example, published European patent Application No. 0 372 777 (EPO89312270.5) describes the use of 1,1,1,2-tetrafluoroethane (HFC-134(a)) in combination with at least one "adjuvant" (a compound having a higher polarity than the HFC-134(a)) and a surface active agent to prepare suspension and solution formulations of medicaments suitable for administration by the aerosol route. Also, PCT Published Application No. W091/11496 (PCT/EP91/00178) discloses the use of 1,1,1,2,3,3,3-heptafluoropropane (HFC-227), optionally mixed with other propellant components, for use in preparing suspension aerosol formulations of medicaments.
  • US-A-2 868 641 and US-A-3 282 781 disclose aerosol compositions comprising a medicament (epinephrine or isoproterenol HCl), a cosolvent, a propellant and ascorbic acid as anti-oxidant.
  • It has now been found that the use of propellant systems containing an HFC and a cosolvent in aerosol solution formulations presents a chemical stability problem that has not been previously recognized or resolved in the prior art. This is because in such HFC propellant/cosolvent systems, the medicament may interact with the cosolvent and/or water present in the system to produce decomposition or degradation products. It has now further been found that the addition of an acid, either an inorganic acid or an organic acid, to the HFC propellant/cosolvent system provides the requisite chemical stability to the medicament.
    • DESCRIPTION OF THE INVENTION
  • The term "aerosol suspension formulation" means a pharmaceutical formulation of a medicament suitable for aerosol administration wherein the medicament is suspended, in the form of finely, divided particles, in an excipient.
  • The term "aerosol solution formulation" means a pharmaceutical formulation of a medicament suitable for aerosol administration wherein the medicament and excipients are completely dissolved.
  • The term "stabilized aerosol solution formulation" means an aerosol solution formulation which exhibits substantial chemical stability over time.
  • Ipratropium bromide is an anticholinergic bronchodilator marketed under the trademark "ATROVENT." This medicament is administered as an aerosol suspension formulation which contains a mixture of CFCs (dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane) as the propellant, and soya lecithin.
  • Studies have demonstrated that stable aerosol solution formulations of ipratropium bromide can be obtained by dissolving ipratropium bromide in a homogeneous system comprising HFC-134(a), ethanol, and either an inorganic acid or an organic acid. The particular type and amount of acid added to the system will define the level of acidity which is critical in obtaining a stable solution formulation.
  • Thus, the present invention provides stabilized aerosol solution formulations comprising a medicament, selected from the group consisting of ipratropium bromide, oxitropium bromide, albuterol tiotropium bromide and feneterol an HFC propellant, a cosolvent, and an inorganic acid or an organic acid. A small amount of water (up to about 5% by weight) may also be present in the propellant/cosolvent system.
  • Suitable HFC propellants are those which, when mixed with the cosolvent(s), form a homogeneous propellant system in which a therapeutically effective amount of the medicament can be dissolved. The HFC propellant must be toxicologically safe and must have a vapor pressure which is suitable to enable the medicament to be administered via a pressurized MDI. Additionally, the HFC propellant must be compatible with the components of the MDI device (such as containers, valves, and sealing gaskets, etc.) which is employed to administer the medicament. Preferred HFC propellants are 1,1,1,2-tetrafluoroethane (HFC-134(a)) and 1,1,1,2,3,3,3,-heptafluoropropane (HFC-227). HFC-134(a) is particularly preferred. Other examples of HFC propellants are HFC-32 (difluoromethane), HFC-143(a) (1,1,1-trifluoroethane), HFC-134 (1,1,2,2-tetrafluoroethane), and HFC-152a (1,1-difluoroethane).
  • It will be apparent to those skilled in the art that non-halogenated hydrocarbon propellants may be used in place of the HFC propellants in the present invention. Examples of non-halogenated hydrocarbons are saturated hydrocarbons, including propane, n-butane, and isobutane, and ethers, including diethyl ether.
  • It will also be apparent to those skilled in the art that, although the use of a single HFC propellant is preferred, a mixture of two or more HFC propellants, or a mixture of at least one HFC propellant and one or more non-CFC propellants, may be employed in the aerosol solution formulation of the present invention.
  • A substantially non-aqueous HFC propellant/cosolvent system is preferred. Water may be present in small amounts as an impurity in the HFC propellant/cosolvent system, may be introduced during the manufacturing process or may permeate into the system through the valve or valve/container seals or gaskets. If desired, small amounts of water may be added (up to about 5% by weight) to the HFC/propellant system, for example, to aid in manufacturing.
  • If desired, pharmaceutically acceptable excipients can be included in the aerosol solution formulations of the present invention. For example, a soluble surface active agent can be added in order to improve the performance of valve systems employed in the MDI devices used for the aerosol administration of the formulations. Examples of preferred surface active agents are oleic acid, sorbitan trioleate, lecithin, and isopropylmyristate. Other suitable lubricants are well known in the art (see, for example, Published European Patent Application No. 0372777 (EPO 893122705)). Other excipients are: (a) antioxidants, for example ascorbic acid and tocopherol; (b) taste masking agents, for example, menthol, sweeteners, and artificial or natural flavors; and (c) pressure modifying agents, for example, n-pentane, iso-pentane, neo-pentane, and n-hexane.
  • The medicaments used in the present invention are selected from the group consisting of ipratropium bromide, oxitropium bromide, albuterol, tiotropium bromide and feneterol. The medicament must be soluble in the HFC propellant/cosolvent system and, characteristically exhibit significant degradation or decomposition in the HFC propellant/cosolvent system. The degradation or decomposition of the medicament must be acid sensitive in that the rate of degradation or decomposition can be effectively reduced by the addition of acid.
  • The decomposition and the degradation of the medicament may occur by various chemical mechanisms, the most significant being interaction of the medicament with the cosolvent or with the water present in the system to form hydrolysis, esterification, and/or ether products.
  • The amount of medicament employed in the aerosol solution formulations of the present invention is that which is effective in producing the intended therapeutic effect, i.e., an amount such that one or more metered volumes of the formulation will deliver an effective amount of the medicament. It will be apparent to those skilled in the art that the potency of the particular medicament employed in the aerosol solution formulation will determine the amount of medicament in the formulation. In general, the medicament is present in an amount from about 0.001 to 10 percent by weight of the total weight of the formulation. An amount of from about 0.01 to 1.0 percent by weight of the total weight of the formulation is preferred.
  • The most preferred example of the medicaments for use in the aerosol solution formulations of the present invention is ipratropium bromide. Other examples are oxitropium bromide (BA253), albuterol, tiotropium bromide (BA-679), and fenoterol hydrobromide.
  • The chemical nature of the medicament defines the nature of the cosolvent, which may be any one of a number of organic solvents that are toxicologically safe and amenable to MDI solution formulations. By "cosolvent" is meant any solvent which is miscible in the formulation in the amount desired and which, when added provides a formulation in which the medicament can be dissolved in therapeutically effective amounts. Examples of cosolvents that contain hydroxyl functions (or other functions) capable of interacting with the medicament(s) in the formulation are: alcohols, for example, ethyl alcohol and isopropyl alcohol; glycols for example, propylene glycol, polyethylene glycols, polypropylene glycols, glycol ethers, and block copolymers of oxyethylene and oxypropylene; and other substances, for example, glycerol, polyoxyethylene alcohols, and polyoxtethylene fatty acid esters.
  • Examples of cosolvents that may be inert to interaction with the medicament(s) are hydrocarbons, for example, n-propane, n-butane, isobutane, n-pentane, iso-pentane, neo-pentane, and n-hexane; and ethers, for example, diethyl ether.
  • A preferred cosolvent according to this invention is ethyl alcohol (ethanol).
  • The function of the cosolvent is to increase the solubility of the medicament and the excipients in the formulation. Thus, the amount of cosolvent present in the formulation defines the maximum amount of medicament and excipients that can be dissolved at a particular temperature.
  • The selection of the acid in the aerosol solution formulations of this invention depends on the medicament used and the acid concentration needed to effect an acceptable rate of degradation of the medicament. Ideally the preferred acid will have the same anion as that contained in the medicament, if any. However, in some instances, this may present solubility limitations. The acid may be any inorganic or mineral acid, for example, hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid, or the like. The acid may also be selected from the group of acids known to those skilled in the art as organic acids, which are in most cases considered to be weak acids relative to the inorganic acids. Representative of this group and preferred in this invention are ascorbic acid and citric acid, although other organic acids may also be suitable. However, according to this invention, citric acid is the most preferred acid because of MDI component compatibility.
  • According to this invention an aerosol solution formulation comprising a particular medicament may be formulated using acids selected from either of the above groups.
  • The methods used to introduce the acid into the formulation may include: (1) the direct addition of the inorganic or organic acid; (2) the addition of the medicament as an acidic salt thereby generating the correct acidity level in situ, and (3) combinations of (1) and (2). Appropriate salts for introducing the medicament into the formulation will be apparent to those skilled in the art.
  • Laboratory experiments have demonstrated that aerosol solution formulations of ipratropium bromide in HFC-134(a) and about 35% ethanol exhibit significant decomposition of the ipratropium bromide when stored at 50°C. The decomposition can be attributed to oxidation, chemical dehydration, hydrolysis and esterification. However, tropic acid ethyl ester is the chief degradation product. This ester can be formed by the direct reaction of ethanol with ipratropium bromide or by hydrolysis of ipratropium bromide followed by esterification of tropic acid with ethanol. Addition of 1% water reduced the decomposition due to dehydration. Carrying out the reaction under nitrogen atmosphere reduced the oxidation products.
  • In aqueous solution the rate of hydrolysis and esterification is typically pH dependent. In aqueous solution, the degradation of ipratropium bromide exhibits a pH-rate minimum at pH 3.5. This corresponds to a hydrogen ion concentration of 3.2 X 10-4 molar (M) at 25°C. Although the concept of pH is poorly defined in non-aqueous systems, formulation evaluation studies were conducted using this concentration of hydrochloric acid in the HFC-134(a)/ethanol system containing ipratropium bromide. Samples stored at 50°C for five and one-half months exhibited less than 5.5% loss of ipratropium bromide. A summary of these results is illustrated in Figure 1.
  • A range of chemical compositions is given in Table 1 for aerosol solution formulations containing ipratropium bromide, HFC-134(a), and an inorganic acid, such as hydrochloric, nitric phosphoric, or sulfuric acid. The amount of alcohol present in the formulation defines the maximum amount of ipratropium bromide that can be dissolved at a particular temperature. The range of ipratropium bromide concentrations given in Table 1 is based on the maximum amount that can be safely dissolved without precipitation at room temperature for a given alcohol concentration. Acid content is given in units of normality which defines a pH range equivalent to 2.0 - 4.7 in an aqueous system.
    Ipratropium Bromide Aerosol Solution Formulations:
    Range Of Chemical Compositions For An Inorganic Acid Formulation
    Component Contents per MDI Container
    Ipratropium Bromide as the Monohydrate 0.001 - 25% wght./wght.
    Dehydrated (Absolute) Ethanol, USP 1.0 - 50.0% wght./wght.
    1,1,1,2-Tetrafluoroethane, (HFC-134(a)) (Dupont Pharmaceutical Toxicity Grade) 50.0 - 99.0% wght./wght.
    Inorganic Acid, USP/NF (Hydrochloric Acid) 0.01 - 0.00002 Normal
    Water (Purified), USP 0.0 - 5.0% wght./wght.
  • A range of chemical compositions is given in Table 2 for aerosol solution formulations containing ipratropium bromide, HFC-134(a), and the organic acid, ascorbic acid. The range of ascorbic acid concentration presented in Table 2 was based on its acid dissociation constant(s), pKa(s), and the optimal pH range for a stable ipratropium bromide formulation (2.0-4.7) in an aqueous system. For ascorbic acid, 0.0045-275 mg/ml would be required to correspond to an aqueous pH range of 2.0-4.7. However, solubility limitations in the formulation must also be taken into consideration given the fact that ascorbic acid is only soluble to about 20 mg/ml in absolute ethanol and is expected to have a lesser solubility in an absolute ethanol/HFC-134(a) system. The information contained in Table 2 is presented for ascorbic acid and gives a range of ethanol content that is based on the expected room temperature solubility of ipratropium bromide (as the monohydrate). Optimally, about 0.30 mg/ml of ascorbic acid is expected to be required in such a formulation corresponding to a pH-degradation rate minimum of pH 3.5 for ipratropium bromide in an aqueous system.
  • The range of concentration presented in Table 2 for ascorbic acid will differ for another organic acid depending on its acid dissociation constant(s). For example about 0.0039-27.7 mg/ml of citric acid would be required in the formulation corresponding to an optimal aqueous pH range of 2.0-4.7 for ipratropium bromide.
  • The range of acid concentration required to effect an acceptable rate of decomposition for medicaments in primarily non-aqueous solution aerosol formulations will depend primarily on the chemical composition of the formulation (such as choice of cosolvent(s) and the chemical nature of the medicaments(s) present). This range is expected to be about 0.10 - 0.0000001 normal for the inorganic acids corresponding to an aqueous pH range of about 1.0-7.0 and must be calculated for the organic acids depending on their pKa values.
    Ipratropium Bromide Aerosol Solution MDI Formulations:
    Range Of Chemical Compositions For An Organic Acid Formulation
    Component Contents per Container
    Ipratropium Bromide as the Monohydrate 0.001 - 2.5% wght./wght.
    Dehydrated (Absolute) Ethanol, USP 1.0 - 50.0% wght./wght.
    1,1,1,2-Tetrafluoroethane, (HFC-134(a)) (Dupont Pharmaceutical Toxicity Grade) 50.0 - 99.0% wght./wght.
    Ascorbic Acid, USP 0.00015 - 5.0 mg/ml
    Water (Purified), USP 0.0 - 5.0% wght./wght.
  • Preferred examples of chemical compositions for aerosol solution formulations containing ipratropium bromide, HFC-134(a) and citric acid are shown in Table 3. The standard amount of ipratropium bromide in an MDI which is considered to supply an effective dosage is indicated as "regular strength." However, dosages of half strength and double strength are also preferred. The range of citric acid concentration presented in Table 3 was based on its acid dissociation constant(s), pKa(s), and optimal pH range for a stable ipratropium bromide formulation (2.0-4.7) in an aqueous system.
    Ipratropium Bromide Aerosol Solution Formulations Containing Citric Acid
    Contents per MDI Container
    Component Half Strength Regular Strength Double Strength
    Ipratropium Bromide as the Monohydrate 0.0187% wght./wght. 0.0374% wght./wght. 0.0748% wght./wght.
    Dehydrated (Absolute) Ethanol, USP 15.0000% wght./wght. 15.0000% wght./wght. 15.0000% wght./wght.
    1,1,1,2-Tetrafluoroethane, (HFC-134(a)) (Dupont Pharmaceutical Toxicity Grade) 84.4773% wght./wght. 84.4586% wght./wght. 84.4212% wght./wght.
    Citric Acid, USP 0.0040% wght./wght. 0.0040% wght./wght. 0.0040% wght./wght.
    Water (Purified), USP 0.5000% wght./wght. 0.5000% wght./wght. 0.5000% wght./wght.
    Total 100.0000% 100.0000% 100.0000%
  • As another preferred example, Table 4 gives a chemical composition for an aerosol formulation containing fenoterol hydrobromide, HFC-134(a) and citric acid.
    Fenoterol Hydrobromide Aerosol Solution Formulation
    Component Contents per MDI Container
    Fenoterol Hydrobromide 0.192% wght./wght.
    Dehydrated (Absolute) Ethanol, USP 30.000% wght./wght.
    1,1,1,2-Tetrafluoroethane, (HFC-134(a)) (Dupont Pharmaceutical Toxicity Grade) 67.806% wght./wght.
    Citric Acid, USP 0.002% wght./wght.
    Water (Purified), USP 2.000% wght./wght.
    Total 100.000%
  • The amount of drug in an aerosol solution formulation that can be delivered through the valve of an MDI will depend on the activeingredient concentration (mg/ml) in the formulation and the metering volume (ul) of the valve. Commonly used valve sizes are 25, 50, 63 and 100 ul.
  • Metered dose inhalers containing aerosol solution formulations of medicaments can be manufactured using a number of conventional processing methods. One method, which is useful in the laboratory for the manufacture of small laboratory scale lots, is Dual Stage Pressure Fill. This method is shown in Tables 5 and 6 for two specific ipratropium bromide solution formulations using a 50-ul valve. Two methods for large scale manufacture are Single-Stage Cold Fill and Single-Stage Pressure Fill.
    Ipratropium Bromide Inhalation Aerosol, 0.021 mg Drug Delivered Through The Valve, 12 ml
    I. Composition
    Component Contents per Container
    Ipratropium Bromide Monohydrate 0.00505 gm
    Dehydrated (Absolute) Ethyl Alcohol, USP 2.02500 gm
    1,1,1,2-Tetrafluoroethane, (HFC-134(a) (Dupont Pharmaceutical Toxicity Grade) 11.40209 gm
    Nitric Acid, USP/NF 0.00036 gm
    Water (Purified), USP 0.06750 gm
    TOTAL: 13.50000
    II. Device Components
    Suitable Aerosol Container
    50 ul Aerosol Metering Valve
    III. Brief Description of Processing Method
    An active ingredient concentrate is prepared by dissolving the ipratropium bromide, as the monohydrate, nitric acid, and water in ethyl alcohol. The concentrate is added to an appropriate filling apparatus. The active ingredient concentrate is dispensed into aerosol containers. The headspace of the containers is purged with nitrogen or HFC-134(a) vapor (purging ingredients should not contain more than 1 ppm oxygen) and is sealed with valves. The HFC-134(a) propellant is then pressure-filled into the sealed containers.
    Ipratropium Bromide Inhalation Aerosol, 0.021 mg Drug Delivered Through The Valve 12 ml
    I. Composition
    Component Stated Contents Per Container
    Ipratropium Bromide Monohydrate 0.00505 gm
    Dehydrated (Absolute) Ethyl Alcohol, USP 2.02500 gm
    1,1,1,2-Tetrafluoroethane (HFC-134A), (Dupont Pharmaceutical Toxicity Grade) 11.26745 gm
    Ascorbic Acid, USP 0.13500 gm
    Water (Purified), USP 0.06750 gm
    TOTAL: 13.50000
    II. Device Components:
    Suitable Aerosol Container
    50 ul Aerosol Metering Valve
    III. Brief Description of Processing Method
    An active ingredient concentrate is prepared by dissolving the ipratropium bromide, as the monohydrate, ascorbic acid and water in ethyl alcohol. The concentrate is added to an appropriate filling apparatus. The active ingredient concentrate is dispensed into aerosol containers, the headspace of the containers is purged with Nitrogen or HFC-134(a) vapor (purging ingredients should not contain more than 1 ppm oxygen) and is sealed with valves. The HFC-134(a) propellant is then pressure filled into the sealed containers.

Claims (16)

  1. An aerosol solution formulation comprising a medicament, selected from the group consisting of ipratropium bromide, oxitropium bromide, albuterol, tiotropium bromide and fenoterol, an HFC propellant, an organic cosolvent, and either an inorganic or an organic acid wherein the medicament chemically degrades or decomposes by interaction with the cosolvent or water or other mechanism, such chemical degradation having the capability of being reduced to acceptable levels by the addition of the inorganic or organic acid, and wherein the acid is present in an amount sufficient to reduce the chemical degradation to an acceptable level.
  2. An aerosol solution formulation according to Claim 1 wherein the HFC propellant is 1,1,1,2-tetrafluoroethane.
  3. An aerosol solution formulation according to Claim 1 wherein the HFC propellant is 1,1,1,2,3,3,3-heptafluoropropane.
  4. An aerosol solution formulation according to Claim 2 or 3 wherein the organic cosolvent is ethyl alcohol.
  5. An aerosol solution formulation according to Claim 4 wherein the ethyl alcohol is in the range of about 1.0 to 50.0 % wght./wght. of the formulation.
  6. An aerosol solution formulation according to Claim 5 wherein the inorganic acid is selected from the group consisting of sulfuric acid, hydrochloric acid, nitric acid, and phosphoric acid.
  7. An aerosol solution formulation according to claim 5 wherein the organic acid is selected from the group consisting of ascorbic acid and citric acid.
  8. An aerosol solution formulation according to Claim 5 which contains water in an amount up to about 5.0 % wght./wght.
  9. An aerosol solution formulation comprising ipratropium bromide, an HFC propellant, ethyl alcohol and an inorganic acid or an organic acid wherein the ipratropium bromide chemical degradation by interaction with cosolvent or water is reduced to acceptable levels by the addition of the inorganic or organic acid to the aerosol solution formulation.
  10. An aerosol solution formulation according to Claim 9 wherein the HFC propellant is 1,1,1,2-tetrafluoroethane.
  11. An aerosol solution formulation according to claim 9 wherein the HFC propellant is 1,1,1,2,3,3,3-heptafluoropropane.
  12. An aerosol solution formulation according to claim 10 or 11 wherein the ethyl alcohol is within the range of about 1.0 to 50.0 % wght./wght.
  13. An aerosol solution formulation according to Claim 10 or 11 wherein the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.
  14. An aerosol solution formulation according to claim 13 wherein the inorganic acid is within the range of about 0.00002 to 0.01 Normal.
  15. An aerosol solution formulation according to Claim 10 or 11 wherein the organic acid is selected from the group consisting of ascorbic acid and citric acid.
  16. An aerosol solution formulation according to claim 15 wherein the organic acid is ascorbic acid and which is within the range of about 0.0045 to 5.0 mg/ml or is citric acid and which is within the range of about 0.0039 to 27.7 mg/ml.
EP94903467A 1992-12-09 1993-12-06 Stabilized medicinal aerosol solution formulations Revoked EP0673240B1 (en)

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